Process for the preparation of indolizine derivatives

ABSTRACT

A new process for preparing a compound of the formula: ##STR1##

This application is a 371 of PCT/US94/01465 filed Sep. 6, 1994.

The present invention relates to a new process for the preparation ofindolizine derivatives which have pharmacological activities such asinhibitory activity on testosterone 5α-reductase and the like.

The process of the present invention is characterized by reacting acompound of the formula: ##STR2## wherein R² is hydrogen, lower alkyl orhalogen, R³ is aryl or ar(lower)alkyl, each of which may have suitablesubstituent(s), substituted carbamoyl(lower)alkyl, or a group of theformula: ##STR3## in which ##STR4## is heterocyclic group containingnitrogen atom, and n is 0 or 1,

Q is carbonyl or lower alkylene,

X is ##STR5## in which R⁴ is hydrogen or lower alkyl, and R⁵ ishydrogen, lower alkyl or Y--Z--R³,

Y is bond or lower alkylene, and

Z is lower alkylene, lower alkenylene, --O-- or ##STR6## in which R⁶ ishydrogen, lower alkyl, ar(lower)alkyl which may have suitablesubstituent(s) or amino protective group,

or a salt thereof, with a compound of the formula: ##STR7## wherein R¹is carboxy or protected carboxy, R¹¹ is hydrogen or lower alkyl,

A is lower alkylene which may be substituted by oxo, or loweralkenylene, and

W¹¹ is acid residue,

or a salt thereof, to give a compound of the formula: ##STR8## whereinR¹, R², R³, R¹¹, A, Q, X, Y and Z are each as defined above,

or a salt thereof.

The process of the present invention is very useful for industriallypreparing the indolizine derivatives.

Suitable salts of the compounds (I), (II) and (III) are conventionalnon-toxic, pharmaceutically acceptable salt and may include a salt witha base or an acid addition salt such as a salt with an inorganic base,for example, an alkali metal salt (e.g. sodium salt, potassium salt,cesium salt, etc.), an alkaline earth metal salt (e.g. calcium salt,magnesium salt, etc.), an ammonium salt; a salt with an organic base,for example, an organic amine salt (e.g. triethylamine salt, pyridinesalt, picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), etc.;an inorganic acid addition salt (e.g. hydrochloride, hydrobromide,sulfate, phosphate, etc.); an organic carboxylic or sulfonic acidaddition salt (e.g. formate, acetate, trifluoroacetate, maleate,tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.);a salt with a basic or acidic amino acid (e.g. arginine, aspartic acid,glutamic acid, etc.); and the like, and the preferable example thereofis an acid addition salt.

In the above and subsequent descriptions of the present specification,suitable examples and illustrations of the various definitions which thepresent invention include within the scope thereof are explained indetail as follows.

The term "lower" is intended to mean 1 to 6 carbon atoms, preferably 1to 4 carbon atoms, unless otherwise indicated.

Suitable "lower alkyl" may include straight or branched one, having 1 to10 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and thelike, preferably one having 1 to 6 carbon atoms, and more preferably onehaving 1 to 4 carbon atoms.

The term "halogen" means fluoro, chloro, bromo and iodo.

Suitable "lower alkylene" means straight or branched bivalent loweralkane such as methylene, ethylene, trimethylene, tetramethylene,pentamethylene, hexamethylene, propylene, and the like, which may besubstituted by oxo.

Suitable "acid residue" may include halogen (e.g. fluoro, chloro, bromo,iodo), acyloxy (e.g. acetoxy, tosyloxy, mesyloxy, etc.) and the like.

Suitable "lower alkenylene" may include one having 2 to 6 carbon atomssuch as vinylene, propenylene, and the like.

Suitable "aryl which may have suitable substituent(s)" may include aconventional group such as aryl (e.g. phenyl, naphthyl, etc.),substituted aryl, for example, lower alkylaryl (e.g. tolyl, xylyl,mesityl, cumenyl, isobutylphenyl, etc.), haloaryl (e.g. chlorophenyl,etc.), and the like.

"Ar(lower)alkyl" in the "ar(lower)alkyl which may have suitablesubstituent(s)" means straight or branched C₁ -C₁₀ alkyl substituted byaryl group(s), and suitable "ar(lower)alkyl which may have suitablesubstituent(s)" may include a conventional group such as ar(lower)alkyl(e.g. trityl, benzhydryl, benzyl, phenethyl, naphthylmethyl,1-phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl,phenylheptyl, phenyLoctyl, phenyldecyl, 2,2-dimethyl-1-phenylpropyl,etc.), substituted ar(lower)alkyl!, for example, ar(lower)alkylsubstituted by one or more substituents such as lower alkyl as mentionedabove, halogen as mentioned above, cyano, carboxy, protected carboxy asmentioned below, aryl which may have suitable substituent(s) asmentioned above, amidated carboxy as mentioned below, lower alkoxy (e.g.methoxy, ethoxy, propoxy, etc.), hydroxy(lower)alkyl (e.g.hydroxyisobutyl, etc.), protected hydroxy(lower)alkyl as loweralkanoyloxy(lower)alkyl (e.g. acetoxyisobutyl, etc.),cyclo(lower)alkyl(lower)alkyl (e.g. cyclopropylmethyl),cyclobutylmethyl, etc.), lower alkenyl (e.g. vinyl, propenyl, butenyl,etc.), and lower alkynyl (e.g. ethynyl, propynyl, butynyl, etc.).Specific examples of thus defined "ar(lower)alkyl which may havesuitable substituents" may be methylbenzyl, isobutylbenzyl,(methylphenyl)ethyl, (isobutylphenyl)ethyl, (methylphenyl)propyl,(isobutylphenyl)propyl, (isobutylphenyl)butyl, (methylphenyl)pentyl,(isobutylphenyl)pentyl, (isobutylphenyl)hexyl, (isobutylphenyl)heptyl,(isobutylphenyl)octyl, bis(methylphenyl)methyl, bis(propylphenyl)methyl,bis(butylphenyl)methyl, bis(isobutylphenyl)methyl,bis(chlorophenyl)methyl, (cyano) (isobutylphenyl)methyl, (carboxy)(isobutylphenyl)methyl, (benzyloxycarbonyl) (isobutylphenyl)methyl,(N,N-diethylcarbamoyl) (isobutylphenyl)methyl, (t-butylcarbamoyl)(isobutylphenyl)methyl, (phenylcarbamoyl) (isobutylphenyl)methyl,(isobutylphenylcarbamoyl) (isobutylphenyl)methyl, (butylcarbamoyl)(isobutylphenyl)methyl, (heptylcarbamoyl) (isobutylphenyl)methyl,(ethoxy) (isobutylphenyl)ethyl, (isobutylphenyl)trifluorobutyl, (phenyl)(isobutylphenyl)methyl, (isobutyl) (methoxy)phenyl!pentyl, (fluoro)(isobutyl)phenyl!pentyl, (fluoro) (hydroxyisobutyl)phenyl!pentyl,(fluoro) (acetoxyisobutyl)phenyl!pentyl,(cyclopropylmethylphenyl)butenyl, (isobutylphenyl)butynyl,(isobutylphenyl)butenyl, (isobutylphenyl)pentenyl, etc.!, and the like.

Suitable "amino protective group" may be a conventional protectivegroup, which is used in the field of organic chemistry, that is, mayinclude acyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.),lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, etc.), and the like.

Suitable "protected carboxy" may include an esterified carboxy group.

Suitable examples of the ester moiety of an "esterified carboxy" may bethe ones such as lower alkyl ester (e.g. methyl ester, ethyl ester,propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butylester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.) whichmay have at least one suitable substituent(s), for example, loweralkanoyloxy(lower)alkyl ester (e.g. acetoxymethyl ester,propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethylester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1(or2)-acetoxyethyl ester, 1(or 2 or 3)-acetoxypropyl ester, 1(or 2 or 3 or4)-acetoxybutyl ester, 1(or 2)-propionyloxyethyl ester, 1(or 2 or3)-propionyloxypropyl ester, 1(or 2)-butyryloxyethyl ester, 1(or2)-isobutyryloxyethyl ester, 1(or 2)-pivaloyloxyethyl ester, 1(or2)-hexanoyloxyethyl ester, isobutyryloxymethyl ester,2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1(or2)-pentanoyloxyethyl ester, etc.), lower alkanesulfonyl(lower)alkylester (e.g. 2-mesylethyl ester, etc.), mono(or di ortri)-halo(lower)alkyl ester (e.g. 2-iodoethyl ester,2,2,2-trichloroethyl ester, etc.), lower alkoxycarbonyloxy(lower)alkylester (e.g. methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethylester, 2-methoxycarbonyloxyethyl ester, 1-ethoxycarbonyloxyethyl ester,1-isopropoxycarbonyloxyethyl ester, etc.), phthalidylidene(lower)alkylester, or (5-lower alkyl-2-oxo-1,3-dioxol-4-yl) (lower)alkyl ester (e.g.(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.; lower alkenyl ester(e.g. vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g. ethynylester, propynyl ester, etc.); ar(lower)alkyl ester which may have atleast one suitable substituent(s) (e.g. benzyl ester, 4-methoxybenzylester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydrylester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester4-hydroxy-3,5-di-tert-butylbenzyl ester, etc.); aryl ester which mayhave at least one suitable substituent(s) (e.g. phenyl ester,4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester,mesityl ester, cumenyl ester, etc.); phthalidyl ester; and the like.

Preferable examples of the esterified carboxy as mentioned above mayinclude lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, tert-pentyloxycarbonyl,hexyloxycarbonyl, 1-cyclopropylethoxycarbonyl, etc.).

Suitable "heterocyclic group containing nitrogen atom" may includesaturated or unsaturated monocyclic or polycyclic heterocyclic groupcontaining at least one nitrogen atom. Especially preferableheterocyclic group may be 5- or 6-membered aliphatic heteromonocyclicgroup (e.g. morpholinyl, pyrrolidinyl, imidazolidinyl, piperidyl,piperazinyl, etc.), unsaturated condensed heterocyclic group such asdibenzo 6- or 7-membered unsaturated!heteromonocyclic group (e.g.phenoxazinyl, phenothiazinyl, 10,11-dihydro-5H-dibenzoazepinyl, etc.),and the like.

Suitable "substituted carbamoyl(lower)alkyl" meanscarbamoyl(lower)alkyl, in which the carbamoyl moiety is substituted byone or two substituent(s), and suitable substituent may include aconventional group such as lower alkyl as mentioned above, aryl whichmay have suitable substituent(s) as mentioned above. Specific examplesof thus defined "substituted carbamoyl(lower)alkyl" may bebutylcarbamoylmethyl, 1-(heptylcarbamoyl)ethyl,isobutylphenylcarbamoylmethyl, 1-(isobutylphenylcarbamoyl)ethyl, and thelike.

Particularly, the preferred embodiments of R¹, R², R³, R¹¹, A, Q, X, Yand Z are as follows.

R¹ is carboxy;

esterified carboxy such as lower alkoxycarbonyl, more preferably C₁ -C₄alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, etc.); orar(lower)alkoxycarbonyl, more preferably mono- or di- or triphenyl(C₁-C₄)-alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.)

R² is hydrogen;

lower alkyl, more preferably C₁ -C₄ alkyl (e.g. methyl, etc.); orhalogen (e.g. chloro, etc.),

R³ is aryl which may be substituted by lower alkyl, more

preferably phenyl substituted by C₁ -C₄ alkyl (e.g. isobutylphenyl,etc.); ar(lower)alkyl which may be substituted by one or moresubstituents selected from the group consisting of lower alkyl, halogen,cyano, carboxy, protected carboxy, amidated carboxy, lower alkoxy,hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, cyclo(lower)alkyl,lower alkenyl, and lower alkynyl, more preferably mono- or di- ortriphenyl(lower)alkyl which may be substituted by one to four groupsselected from lower alkyl, halogen, cyano, carboxy,phenyl(lower)alkoxycarbonyl, mono or di(lower)alkylcarbamoyl,phenylcarbamoyl, lower alkylphenylcarbamoyl, lower alkoxy,hydroxy(lower)alkyl, lower alkanoyloxy(lower)alkyl,cyclo(lower)alkyl(lower)alkyl, lower alkenyl, and lower alkynyl, mostpreferably mono- or di- or triphenyl(C₁ -C₁₀)alkyl which may besubstituted by one to four groups selected from (C₁ -C₁₀)alkyl, halogen,cyano, carboxy, phenyl(C₁ -C₄)alkoxycarbonyl, mono or di(C₁-C₁₀)alkylcarbamoyl, phenylcarbamoyl, (C₁ -C₄)alkylphenylcarbamoyl, (C₁-C₄)alkoxy, hydroxy(C₁ -C₄)alkyl, (C₁ -C₄)alkanoyloxy(C_(l) -C₄)alkyl,cyclo(C₃ -C₆)alkyl(C₁ -C₄)alkyl, (C₂ -C₄)alkenyl and (C₂ -C₄)alkynyl,(e.g. benzyl, isobutylbenzyl, (isobutylphenyl)ethyl,(isobutylphenyl)propyl, (isobutylphenyl)butyl, (isobutylphenyl)pentyl,(isobutylphenyl)hexyl, (isobutylphenyl)heptyl, (isobutylphenyl)octyl,bis(isobutylphenyl)methyl, bis(chlorophenyl)methyl, (cyano)(isobutylphenyl)methyl, (carboxy) (isobutylphenyl)methyl,(benzyloxycarbonyl) (isobutylphenyl)methyl, (N,N-diethylcarbamoyl)(isobutylphenyl)methyl, (t-butylcarbamoyl) (isobutylphenyl)methyl,(phenylcarbamoyl) (isobutylphenyl)methyl, (isobutylphenylcarbamoyl)(isobutylphenyl)methyl, (butylcarbamoyl) (isobutylphenyl)methyl,(heptylcarbamoyl) (isobutylphenyl)methyl, (ethoxy)(isobutylphenyl)ethyl, (isobutylphenyl) (trifluoro)butyl, (phenyl)(isobutylphenyl)methyl, (isobutyl) (methoxy)phenyl!pentyl, (fluoro)(isobutyl)phenyl!pentyl, (fluoro) (hydroxyisobutyl)phenyl!pentyl,(fluoro) (acetoxyisobutyl)phenyl!pentyl,(cyclopropylmethylphenyl)butenyl, (isobutylphenyl)butynyl,(isobutylphenyl)butenyl, (isobutylphenyl)pentenyl, etc.);carbamoyl(lower)alkyl, in which he carbamoyl moiety is substituted byone or two substituent(s) selected from the group consisting of loweralkyl and lower alkylphenyl, more preferably (C₁ -C₁₀)alkylcarbamoyl-(C₁-C₄)alkyl or (C₁ -C₄)alkylphenylcarbamoyl(C₁ -C₄)-alkyl (e.g.heptylcarbamoylethyl, isobutylphenylcarbamoylmethyl,isobutylphenylcarbamoylethyl, etc.); 5- or 6-membered aliphaticheteromonocycliccarbonyl (e.g. piperidylcarbonyl, etc.); or unsaturatedcondensed heterocyclic group (e.g. phenoxazinyl, phenothiazinyl,10,11-dihydro-5H-dibenzo b,f!azepinyl, etc.),

R¹¹ is hydrogen; or lower alkyl, more preferably C₁ -C₄

alkyl (e.g. methyl, etc.),

A is lower alkylene which may be substituted by oxo, more

preferably C₁ -C₄ alkylene which may be substituted by oxo (e.g.ethylene, trimethylene, oxotrimethylene, etc.); or lower alkenylene,more preferably C₂ -C₄ alkenylene (e.g. propenylene, etc.),

Q is carbonyl; or

lower alkylene, more preferably C₁ -C₄ alkylene (e.g. methylene, etc.),

X is ##STR9## in which R⁴ is hydrogen; or lower alkyl, more preferablyC₁ -C₄ alkyl (e.g. meLhyl, etc.),

R⁵ is hydrogen; lower alkyl, more preferably C₁ -C₄ alkyl (e.g. methyl,etc.); or ar(lower)alkylamino which may be substituted by the group(s)selected from lower alkyl or lower alkoxycarbonyl, more preferably C₁-C₄ alkylbenzylamino or N-C₁ -C₄ alkoxycarbonyl-N-C₁ -C₄alkylbenzylamino (e.g. isobutylbenzylamino,N-t-butoxy-carbonyl-N-isobutylbenzylamino, etc.),

Y is bond; or

lower alkylene, more preferably C₁ -C₄ alkylene (e.g. methylene, etc.),and

Z is lower alkylene, more preferably C₁ -C₄ alkylene (e.g.

methylene, etc.); lower alkenylene, more preferably C₂ -C₄ alkenylene(e.g. vinylene, etc.);

--O--; or ##STR10## in which R⁶ is hydrogen; lower alkyl, preferably C₁-C₄ alkyl (e.g. methyl, ethyl, etc.); lower alkoxycarbonyl, preferablyC₁ -C₄ alkoxycarbonyl (e.g. t-butoxycarbonyl, etc.); ar(lower)alkylwhich may be substituted by lower alkyl, more preferably mono- or di- ortriphenyl(lower)alkyl which may be substituted by lower alkyl, mostpreferably mono- or di- or triphenyl(C₁ -C₆)alkyl which may besubstituted by C₁ -C₄ alkyl (e.g. benzyl, isobutylbenzyl, etc.).

The process for preparing the object compound (I) of the presentinvention is explained in detail in the following.

PROCESS

The object compound (I) or a salt thereof can be prepared by reactingthe compound (II) or a salt thereof with the compound (III) or a saltthereof.

This reaction is usually carried out in a solvent such as alcohol e.g.methanol, ethanol, etc.!, dichloromethane, benzene,N,N-dimethylformamide, tetrahydrofuran, diethyl ether or any othersolvent which does not adversely affect the reaction.

The reaction may be carried out in the presence of an inorganic or anorganic base such as an alkali metal hydroxide e.g. sodium hydroxide,potassium hydroxide, etc.!, an alkali metal carbonate e.g. sodiumcarbonate, potassium carbonate, etc.!, an alkali metal bicarbonate e.g.sodium bicarbonate, potassium bicarbonate, etc.!, alkali metal hydride(e.g. sodium hydride, potassium hydride, etc.), tri(lower)alkylaminee.g. trimethylamine, triethylamine, diisopropylethylamine, etc.!,pyridine or its derivative e.g. picolin, lutidine,4-dimethylaminopyridine, etc.!, or the like. In case that the base to beused is liquid, it can also be used as a solvent.

The reaction temperature is not critical, and the reaction can becarried out under cooling, at room temperature or under warming orheating.

The object compound (I) of the present invention can be isolated andpurified in a conventional manner, for example, extraction,precipitation, fractional crystallization, recrystallization,chromatography, and the like.

The object compound (I) thus obtained can be converted to its salt by aconventional method.

The object compound (I) of the present invention is useful as atestosterone 5α-reductase inhibitor and effective to testosterone5α-reductase mediated diseases such as prostatism, prostatichypertrophy, prostatic cancer, alopecia, hirsutism (e.g. femalehirsutism, etc.), androgenic alopecia (or male-pattern baldness), acne(e.g. acne vulgaris, pimple etc.), other hyperandrogenism, and the like.

For therapeutic or preventive administration, the object compound (I) ofthe present invention are used in the form of conventionalpharmaceutical preparation which contains said compound as an activeingredient, in admixture with pharmaceutically acceptable carriers suchas an organic or inorganic solid or liquid excipient which is suitablefor oral, parenteral and external administration. The pharmaceuticalpreparation may be in solid form such as tablet, granule, powder,capsule, or liquid form such as solution, suspension, syrup, emulsion,lemonade, lotion and the like.

If needed, there may be included in the above preparations auxiliarysubstances, stabilizing agents, wetting agents and other commonly usedadditives such as lactose, citric acid, tartaric acid, stearic acid,magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin,agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, andthe like.

While the dosage of the compound (I) may vary from and also depend uponthe age, conditions of the patient, a kind of diseases or conditions, akind of the compound (I) to be applied, etc. In general amounts between0.01 mg and about 500 mg or even more per day may be administered to apatient. An average single dose of about 0.05 mg, 0.1 mg, 0.25 mg, 0.5mg, 1 mg, 20 mg, 50 mg, 100 mg of the object compound (I) of the presentinvention may be used in treating diseases.

The following Preparations and Examples are given for the purpose ofillustrating the present invention.

PREPARATION 1

To a solution of adipic acid monomethyl ester (8.0 g) in carbontetrachloride (5 ml) was added thionyl chloride (14.4 ml). The mixturewas stirred at 65° C. for 30 minutes. N-Bromosuccinimide (10.7 g),carbon tetrachloride (25 ml) and 48; hydrobromic acid aqueous solution(0.5 ml) was added to the mixture. The mixture was refluxed for 1.5hours, cooled at room temperature and filtered off. The filtrate wasevaporated and distillated at reduced pressure to give methyl5-bromo-5-chloroformylpentanoate as an oil (9.02 g).

bp : 87°-91° C./0.5 mmHg

NMR (CDCl₃, δ) : 4.55 (1H, m), 3.70 (3H, s), 2.40 (2H, t, J=7Hz),2.0-2.3 (2H, m), 1.6-2.0 (2H, m)

PREPARATION 2

To a solution of methyl 5-bromo-5-chloroformylpentanoate (2.57 g) indiethyl ether (15 ml) was added a mixture of phenol (0.94 g) anddiisopropylethylamine (1.30 g) in diethyl ether (10 ml). The mixture wasstirred at room temperature for 15 minutes and poured into ice water anddiluted hydrochloric acid. The organic layer was washed with water,dried over magnesium sulfate and evaporated. The residue waschromatographed on silica gel eluting with a mixture of n-hexane andethyl acetate (5:1) to give methyl 5-bromo-5-phenoxycarbonylpentanoateas an oil (2.33 g).

NMR (CDCl₃, δ) : 7.3-7.5 (2H, m), 7.2-7.3 (1H, m), 7.1-7.2 (2H, m), 4.43(1H, m), 3.70 (3H, s), 2.40 (2H, t, J=7Hz), 2.1-2.4 (2H, m), 1.7-2.0(2H, m)

PREPARATION 3

To a solution of methyl S-bromo-5-phenoxycarbonyl-pentanoate (1.0 g) intetrahydrofuran (20 ml) was added a 1.0M solution of lithiumtri-tert-butoxyaluminohydride in tetrahydrofuran (3.1 ml) at 0° C. Themixture was stirred for 2 hours and poured into a mixture of dilutedhydrochloric acid and ethyl acetate. The organic layer was washed withbrine, dried over magnesium sulfate and evaporated. The residue waschromatographed on silica gel eluting with a mixture of n-hexane andethyl acetate (5:1) to give methyl 5-bromo-5-formylpentanoate as an oil(0.64 g).

NMR (CDCl₃, δ) : 9.47 (1H, d, J=3Hz), 4.25 (1H, m), 3.68 (3H, s), 2.40(2H, t, J=7Hz), 1.7-2.2 (4H, m)

PREPARATION 4

To a solution of 1-(R)-(4-isobutylphenyl)butanol (1.13 g), methyl4-hydroxybenzoate (917 mg) and triphenylphosphine (1.58 g) in toluene(40 ml) and tetrahydrofuran (10 ml) was added diethyl azodicarboxylate(0.95 ml) at -20° C. The mixture was stirred at -15°--20° C. for 1.5hours and then added water (0.5 ml). The mixture was evaporated,dissolved in a mixture of n-hexane and ethyl acetate (4:1), filtered offand evaporated. The residue was chromatographed on silica gel elutingwith a mixture of n-hexane and dichloromethane (1:1) to give methyl 4-1-(S)-(4-isobutylphenyl)butoxy!benzoate as an oil (1.48 g).

NMR (CDCl₃, δ) : 7.89 (1H, d, J=9Hz), 7.22 (2H, d, J=9Hz), 7.10 (2H, d,J=9Hz) , 6.85 (2H, d, J=9Hz), 5.15 (1H, m), 3.83 (3H, s), 2.42 (2H, d,J=7Hz), 1.9-2.0 (1H, m), 1.7-1.9 (2H, m), 1.3-1.6 (2H, m), 0.95 (3H, t,J=7Hz), 0.89 (6H, d, J=7Hz)

PREPARATION 5

To a solution of methyl 4- 1-(S)-(4-isobutylphenyl)-butoxy!benzoate (283mg) and 2-methylpyridine (0.09 ml) in tetrahydrofuran (5 ml) was added1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran(2.7 ml) at 0° C. The mixture was stirred for 18 hours at roomtemperature. Acetic acid (0.18 ml) and ethyl acetate (15 ml) was addedto the mixture. The mixture was washed with water and aqueous solutionof sodium bicarbonate, dried over magnesium sulfate and evaporated. Theresidue was chromatographed on silica gel eluting with a mixture ofn-hexane and ethyl acetate (2:1) to give 4-1-(S)-(4-isobutylphenyl)butoxy!phenyl 2-pyridylmethyl ketone as a yellowoil (216 mg).

NMR (CDCl₃, δ) : 8.52 (1H, d, J=5Hz), 7.94 (2H, d, J=9Hz), 7.5-7.7 (1H,m), 7.0-7.3 (6H, m), 6.88 (2H, d, J=9Hz), 5.15 (1H, m), 4.39 (2H, s),2.44 (2H, d, J=7Hz), 1.9-2.1 (1H, m), 1.7-1.9 (2H, m), 1.3-1.6 (2H, m),0.94 (3H, t, J=7Hz), 0.89 (6H, d, J=7Hz)

EXAMPLE 1

To a solution of 4- 1-(S)-(4-isobutylphenyl)butoxy!-phenyl2-pyridylmethyl ketone (211 mg) and methyl 5-bromo-5-formylpentanoate(123 mg) in 1,4-dioxane (3 ml) was added diisopropylethyl amine (0.1ml). The mixture was stirred at 80° C. for 3.5 hours and poured into amixture of ethyl acetate and diluted hydrochloric acid. The organiclayer was separated, washed with water, dried over magnesium sulfate andevaporated. The residue was chromatographed on silica gel eluting withthe mixture of n-hexane and ethyl acetate (2:1) to give methyl 4- 1- 4-1-(S)-(4-isobutylphenyl)butoxy!benzoyl!lindolizin-3-yl!butyrate as anoil (187 mg).

NMR (CDCl₃, δ) : 8.43 (1H, d, J=9Hz), 7.98 (1H, d, J=7Hz), 7.73 (2H, d,J=9Hz), 7.25 (2H, d, J=9Hz), 7.11 (2H, d, J=9Hz), 7.1-7.2 (1H, m),6.8-7.0 (4H, m), 5.18 (1H, m), 3.68 (3H, s), 2.89 (2H, t, J=7Hz),2.4-2.5 (4H, m), 1.9-2.15 (3H, m), 1.7-1.9 (2H, m), 1.4-1.6 (2H, m),0.98 (3H, t, J=7Hz), 0.90 (6H, d, J=7Hz)

EXAMPLE 2

To a solution of methyl 4- 1- 4-1-(S)-(4-isobutylphenyl)butoxy!benzoyl!indolizin-3-yl!butyrate (182 mg)in ethanol (4 ml) was added 1N aqueous solution of sodium hydroxide (0.6ml). The mixture was stirred at 50° C. for 40 minutes, and then pouredinto a mixture of ethyl acetate and diluted hydrochloric acid. Theorganic layer was separated, washed with water, dried over magnesiumsulfate and evaporated. The residue was crystallized with diisopropylether to give 4- l- 4-l-(S)-(4-isobutylphenyl)butoxy!benzoyl!indolizin-3-yl!butyric acid aswhite powder (89 mg).

NMR (CDCl₃, δ) : 8.42 (1H, d, J=9Hz), 7.96 (1H, d, J=7Hz), 7.72 (2H, d,J=9Hz), 7.05-7.3 (5H, m), 6.8-6.95 (4H, m), 5.16 (1H, m), 2.88 (2H, t,J=7.5Hz), 2.4-2.55 (4H, m), 1.7-2.15 (5H, m), 1.3-1.65 (2H, m), 0.8-1.05(9H, m)

We claim:
 1. A process for preparing a compound of the formula:##STR11## wherein R¹ is carboxy or protected carboxy, R² is hydrogen,lower alkyl or halogen,R³ is aryl or ar(lower)alkyl, each of which maybe optionally substituted; or carbamoyl(lower)alkyl, in which thecarbamoyl moiety is substituted by 1 or 2 substituent(s) selected fromthe group consisting of lower alkyl and lower alkyl phenyl; or a groupof the formula: ##STR12## in which ##STR13## is a heterocyclic groupcontaining nitrogen, and n is 0 or 1, R¹¹ is hydrogen or lower alkyl, Ais lower alkylene which may be substituted by oxo or lower alkylene, Qis carbonyl or lower alkylene, X is ##STR14## in which R⁴ is hydrogen orlower alkyl, and R⁵ is hydrogen, lower alkyl or Y--Z--R³, Y is a directbond or lower alkylene, and Z is lower alkylene, lower alkenylene,##STR15## in which R⁶ is hydrogen, lower alkyl, or ar(lower)alkyl whichmay be optionally substituted or an amino protective group, or a saltthereof, which process comprises: reacting a compound of the formula:##STR16## wherein R², R³, Q, X, Y and Z are each as defined above, or asalt thereof, with a compound of the formula: ##STR17## wherein R¹, R¹¹and A are each as defined above, and W¹¹ is halogen or acyloxy, or asalt thereof.
 2. The process of claim 1, wherein R³ is aryl orsubstituted aryl consisting of phenyl, naphthyl, tolyl, xylyl, mesityl,cumenyl, isobutylphenyl and chlorophenyl.
 3. The process of claim 1,wherein R³ is ar(lower)alkyl and is selected from the group consistingof trityl, benzhydryl, benzyl, phenethyl, naphthylmethyl, 1-phenylethyl,phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, phenyheptyl,phenyloctyl, phenyldecyl and 2,2-dimethyl-1-phenylpropyl.
 4. The processof claim 1, wherein R³ is ar(lower)alkyl which is substituted by loweralkyl, halogen, cyano, carboxy, protected carboxy, aryl, amidatedcarboxy, lower alkoxy, hydroxy(lower)alkyl, protectedhydroxy(lower)alkyl and cyclo(lower)alkyl(lower)alkyl.
 5. The process ofclaim 1, which is effected in the presence of an inert solvent.
 6. Theprocess of claim 1, which is effected in the presence of an organic orinorganic base.
 7. The process of claim 1, wherein said heterocyclicgroup containing nitrogen is selected from the group consisting of 5-and 6-membered aliphatic heteromonocyclic groups and 6- and 7-memberedunsaturated heteromonocyclic groups.
 8. The process of claim 7, whereinsaid 5- and 6-membered aliphatic heteromonocyclic groups are selectedfrom the group consisting of morpholinyl, pyrrolidinyl, imidazolidinyl,piperidyl and piperazinyl.
 9. The process of claim 7, wherein said 6-and 7-membered unsaturated heteromonocylic groups are selected from thegroup consisting of phenoxazinyl, phenothiazinyl, and10,11-dihydro-5H-dibenzoazepinyl.
 10. The process of claim 1, whichcomprises reacting 4-phenyl 2-pyridylmethyl ketone with methyl5-bromo-5-formyl pentanoate to produce methyl 4-benzoyl butyrate.
 11. Acompound of the formula: ##STR18## wherein R² is hydrogen, lower alkylor halogen, R³ is aryl or ar(lower)alkyl, each of which may beoptionally substituted; or carbamoyl(lower)alkyl, in which the carbamoylmoiety is substituted by 1 or 2 substituent(s) selected from the groupconsisting of lower alkyl or lower alkyl phenyl; or a group of theformula: ##STR19## in which ##STR20## is a heterocyclic group containingnitrogen, and n is 0 or 1, Q is carbonyl or lower alkylene, X is##STR21## in which R⁴ is hydrogen or lower alkyl, and R⁵ is hydrogen,lower alkyl or Y--Z--R³,Y is a direct bond or lower alkylene, and Z islower alkylene, lower alkenylene, ##STR22## in which R⁶ is hydrogen,lower alkyl, or ar(lower)alkyl which may be optionally substituted, oran amino protective group, or a salt thereof.
 12. The compound of claim11, wherein said heterocyclic group containing nitrogen is selected fromthe group consisting of 5- and 6-membered aliphatic heteromonocyclicgroups and 6- and 7-membered unsaturated heteromonocyclic groups. 13.The compound of claim 11, wherein said 5- and 6-membered aliphaticheteromonocyclic groups are selected from the group consisting ofmorpholinyl, pyrrolidinyl, imidazolidinyl, piperidyl and piperazinyl.14. The compound of claim 11, wherein said 6- and 7-membered unsaturatedheteromonocylic groups are selected from the group consisting ofphenoxazinyl, phenothiazinyl, and 10,11-dihydro-5H-dibenzoazepinyl. 15.The compound of claim 11, wherein said salt comprises an alkali metalsalt, an alkaline earth metal salt, an ammonium salt, an organic aminesalt, an inorganic acid addition salt, an organic carboxylic or sulfonicacid addition salt, or a salt of a basic or acidic amino acid.